Transient Receptor Potential (TRP) channels are one of the largest group of ion channels that is divided into 6 sub-families (TRPV, TRPM; TRPA, TRPC, TRPP and TRPML). TRP channels are cation-selective channels activated by several physical (temperature, osmolarity and mechanical) and chemical stimuli. TRPM8, which was cloned in 2002, is a non-selective cation channel of the TRP family expressed on a subpopulation of somatic sensory nerves on dorsal root ganglion and trigeminal ganglia that causes sensory nerve excitation. It is activated by mild cold temperatures and synthetic cooling compounds such as menthol, eucalyptol and icilin [McKemy D. D. et al., Nature (2002) 416, 52-58; Peier A. M. et al. Cell (2002) 108, 705-715]. Like several other TRP channels, TRPM8 is also gated by voltage [Nilius B. et al., J. Physiol. (2005) 567, 35-44]. The voltage dependence of TRPM8 is characterized by a strong outward rectification at depolarized transmembrane potential and a rapid and potential-dependent closure at negative membrane potentials. Cooling agents and menthol application shifts the activation curve towards more negative potentials, increasing the possibility for the opening of the channel and boosting inward currents at physiological membrane potentials. Other endogenous factors, such as phospholipase A2 products [Vanden Abeele F. et al., J. Biol. Chem. (2006) 281, 40174-40182], endocannabinoids [De Petrocellis L. et al., Exp. Cell. Res. (2007) 313, 1911-1920] and PIP2 [Rohacs T. et al., Nat. Neurosci. (2005) 8, 626-634] also participate in channel regulation.
There is a lot of direct and indirect evidence of a role of TRPM8 channel activity in diseases such as pain, ischemia and inflammatory disorders. Further, it has been demonstrated that TRP channels transduce reflex signals that are involved in the overactive bladder of patients with damaged or abnormal spinal reflex pathways [De Groat W. C. et al., Urology (1997) 50, 36-52]. TRPM8 is activated by temperatures between 8 and 28° C. and expressed on the primary nociceptive neurons, including bladder urothelium, dorsal root ganglia, A-delta and C-fibers. The intravesical ice water or menthol also induce C-fiber mediated spinal micturition reflex in patients with urgency and urinary incontinence [Everaerts W. et al., Neurol. Urodyn. (2008) 27, 264-73]. Furthermore, TRPM8 is known to regulate Ca2+ concentration influxes in response to cold temperature or pharmacological stimuli. Finally, in a recent paper, the potential role of TRPM8 in cold-induced asthma and in asthma exacerbation has been proposed, suggesting TRPM8 also a relevant target for the management of these pathologies [Xing H. et al., Molecular Pain (2008), 4, 22-30], even a clinical validation of the target is not so far available.
Cold intolerance induced by chemical or thermal cooling closely parallels symptoms seen in a wide range of clinical disorders and thus provide a strong rationale for the investigation and development of novel TRPM8 inhibitors as novel antihyperalgesic or antiallodynic agents. The expression of the channel in brain, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells provide further possibility for therapeutic modulation in a wide range of pathologies. The disorders or diseases that have been proven to be affected by the modulation of TRPM8 are chronic pain, neuropathic pain including cold allodynia and diabetic neuropathy, postoperative pain, osteoarthritic pain, rheumatoid arthritic pain, cancer pain, neuralgia, neuropathies, algesia, nerve injury, migraine, headaches, ischaemia, neurodegeneration, fibromyalgia, stroke, psychiatric disorders, including anxiety and depression, and inflammatory conditions such as itch, irritable bowel syndrome, or respiratory diseases such as asthma, COPD, and pulmonary hypertension, urological disorders such as painful bladder syndrome, interstitial cystitis, detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia, lower urinary tract disorders and lower urinary tract symptoms [Nilius B. et al. Science STKE (2005), 295, re8; Voets T. et al., Nat. Chem. Biol. (2005), 1, 85-92; Mukerji G. et al., Urology (2006), 6, 31-36; Lazzeri M. et al., Ther. Adv. Urol. (2009), 1, 33-42; Nilius B. et al., Biochim. Biophys. Acta (2007), 1772, 805-12; Wissenbach U. et al., Biol. Cell. (2004), 96, 47-54; Nilius B. et al., Physiol. Rev. (2007), 87, 165-217; Proudfoot C. J. et al., Curr. Biol. (2006), 16, 1591-1605].
Along the last few years, several classes of non peptide TRPM8 antagonists have been disclosed. WO 2006/040136, WO 2007/017092, WO 2007/017093, WO 2007/017094, and WO 2007/080109 describe benzyloxy derivatives as TRPM8 antagonists for the treatment of urological disorders; WO 2007/134107 describes phosphorous-bearing compounds as TRPM8 antagonists for the treatment of TRPM8-related disorders; WO 2009/012430 describes sulfonamides for the treatment of diseases associated with TRPM8; WO 2010/103381 describes the use of spirocyclic piperidine derivatives as to TRPM8 modulators in prevention or treatment of TRPM8-related disorders or diseases; and, WO 2010/125831 describes sulfamoyl benzoic acid derivatives as modulators of the TRPM8 receptor and their use in the treatment of inflammatory, pain and urological disorders.
However, the TRPM8 antagonists under active development for selected indications suffer from drawbacks such as low selectivity, which results in side effects due to interference with other channel systems and an unfavourable PK/ADMET profile, which could impair their further development.
A therapeutic area in which there is a particularly high need for the development of further antagonists of TRPM8 is that of urological-related disorders. In fact, the drugs and medications that are available for the treatment of urinary incontinence and disorders are characterized by several side effects. For example, at the moment, the therapy of overactive bladder syndrome is based on drugs affecting peripheral neural control mechanisms or mechanisms acting directly on bladder detrusor smooth muscle contraction, with a wide use of anticholinergic agents. These drugs inhibit parasympathetic nerves exerting a direct spasmolytic effect on the muscle of the bladder. The result of this action is the decrease of intravesicular pressure, an increase in capacity and a reduction in the frequency of bladder contraction. However, the use of anticholinergic agents is associated with serious side effects, such as dry mouth, abnormal visions, constipation and CNS disturbances, that impair the overall patient compliance. The inadequacies of the actual therapies highlight the need for novel, efficacious and safe drugs with fewer side effects.